Learning, which is the modification of behavior in response to experiences, is one of the most characteristic attributes of animals, including humans. An important feature of learning is that it is adaptive. The animal, having learned, responds in ways that improve its survival and reproductive success. Different animals, even of the same species, learn things if they are exposed to different environments.
Another attribute that many animals, including humans, possess is memory of what was once experienced or learned. This attribute has been studied for many decades with much information now available that explains many of its ramifications. For example, memory can be classified as short term memory lasting seconds to minutes or as long term memory lasting days to weeks to years. Short term memory refers to the ability to recall an experience or what was learned for a short period of time. Long term memory refers to the ability to remember an experience or what was learned long after the experience has occurred or long after that which was learned.
A newly acquired experience initially is susceptible to various forms of disruption. With time, however, the new experience becomes resistant to disruption (McGaugh and Herz, Memory Consolidation, Albion, San Francisco, 1972; Tully, T. et al., Cold Spring Harbor Symp. Quant. Biol., 55:203-211 (1990)). This observation has been interpreted to indicate that a labile, short-term memory is xe2x80x9cconsolidatedxe2x80x9d into a more stable, long-term memory.
Learning and/or memory defects impair the ability of an animal to learn and/or remember an experience, which can be detrimental to the survival and reproductive success of the animal. Accordingly, there is considerable interest in developing techniques for treating learning and/or memory defects.
The present invention relates to methods of treating a learning or short term memory defect associated with a defect in the Neurofibromatosis 1 (NF1) protein in an animal (particularly a human or other mammal or vertebrate) in need thereof. The NF1 protein defect is either a diminution in the amount of NF1 protein produced, a diminution in the activity or action of the NF1 protein produced or both a diminution in amount and activity or action of NF1 protein. In one embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein a NF1 compound such as exogenous NF1, NF1 analog, NF1-like moleculeogically active NF1 fragment or NF1 fusion protein. In a second embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein a nucleic acid sequence encoding exogenous NF1, NF1 analog, NF1-like molecule, biologically active NF1 fragment or NF1 fusion protein. In a third embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein an effective amount of a pharmaceutical agent that stimulates cyclic AMP formation in the same manner as NF1. In a fourth embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein a pharmaceutical agent that activates protein kinase A (PKA) activity in the same manner as NF1.
The present invention also relates to methods for screening a pharmaceutical agent for its ability to treat a short term memory defect associated with a defect in the NF1 protein in an animal (particularly a human or other mammal or vertebrate) in need thereof. The method comprises (a) administering a pharmaceutical agent to an animal with a short term memory defect associated with a defect in the NF1 protein; (b) training the animal under conditions appropriate to produce short term memory formation in the animal; (c) assessing short term memory formation in the animal trained in step (b); and (d) comparing short term memory formation assessed in step (c) with short term memory formation produced in the control animal to which said pharmaceutical agent has not been administered. If the short term memory formation assessed in the animal treated with the pharmaceutical agent is greater than the short term memory formation assessed in the control animal, the pharmaceutical agent is identified as one having the ability to treat a short term memory defect associated with a defect in the NF1 protein.
The invention further relates to methods for screening a pharmaceutical agent for its ability to treat a learning defect associated with a defect in the NF1 protein in an animal (particularly a human or other mammal or vertebrate) in need thereof The method comprises (a) administering a pharmaceutical agent to an animal with a learning defect associated with a defect in the NF1 protein; (b) training the animal under conditions appropriate for learning by the animal; (c) assessing learning ability in the animal trained in step (b); and (d) comparing learning ability assessed (c) with learning ability in the control animal to which said pharmaceutical agent has not been administered. If the learning ability assessed in the treated with the pharmaceutical agent is greater than the learning ability assessed in the control animal, the pharmaceutical agent is identified as one having the ability to treat a learning defect associated with a defect in the NF1 protein.